Wed 2022-Jan-26

# Pan-Coronavirus Vaccines

Last October, we noted that NIAID had granted $36 million for the development of a pan-coronavirus vaccine. Time for an report: how’s that working out? ## Current news on the pan-coronavirus vaccine front Back in October, we noted that the NIAID grants were given to University of Wisconsin at Madison, Brigham & Women’s Hospital in Boston, and Duke University. Ironically, the reports we have today come from none of them, though we didn’t dig into exactly why that is. It could well be that they all did the fundamental research, which fed into the clinical trials at Walter Reed which are today’s subject. I hope so. (Later: Apparently not. All those efforts seem to be independent, and today we’re seeing another effort funded mostly by the US Army.) Let’s see what’s going on! ## What’s the sitch? In a word, the sitch is bad. From Our World in Data come disturbing, though predictable, data on death rates and vaccination status. Nearly every media outlest gets confused about this; even this crummy little blog that nobody reads (CLBTNR) has documented the fact: the fraction of dead who are vaccinated tells you nothing, while the fraction of the vaccinated who die is what matters. That is, you shouldn’t care about$\Pr(\mbox{vaccinated} | \mbox{death})$(which would be 100% if 100% of the population were vaccinated, so it’s clearly meaning-free). Instead you should care about$\Pr(\mbox{death} | \mbox{vaccinated}). The relevant knowledge is the chance of dying if you’re vaccinated vs the chance of dying if you’re not! Our World in Data is showing us how to learn this important lesson: • Up top is the time series for US deaths per 100,000 (so it’s normalized to population sizes), over time, and broken down by vax status. (NB: The unvaxed are in a frustratingly difficult to see gray line that is much higher, so be sure to find it.) You can see clearly that, over 2021-Sep through 2021-Dec, the risk to fully vaccinated and fully vaccinated + boosted populations is negligible. Almost all the risk of death is among the unvaccinated. There is something that is cheap (free), easy, and reliable you can do so you’re not in that high-risk group: get vaccinated & boosted! • The lower plot shows us the same data as a bar chart, for the week of 2021-Dec-04. The conclusion is the same, namely that the unvaccinated are at much greater risk. How much more? Aggregating the vaxed groups, we see it’s about 12x: \begin{align*} \mbox{Risk Ratio} &= \frac{\Pr(\mbox{death} | \mbox{unvaxed})}{\Pr(\mbox{death} | \mbox{vaxed})} \\ &= \frac{9.74/100k}{0.71/100k + 0.10/100k} \\ &= \frac{9.74/100k}{0.81/100k} \\ &= 12.02 \end{align*} Something cheap, easy, and reliable can reduce your risk of death by 12x; maybe you should do that thing? Many others have had a few tart thoughts on these data, mostly of the form: “if you think there’s no point to vaccination, we are completely done tolerating your BS”. As this humble blog says right up top that it is devoted to occasional tart thoughts, let’s look at one. Gerry Doyle of Reuters, for example, reminds us that we can do much better, using the example of Singapore: The green part of the pie chart is people who got asymptomatic or mildly symptomatic COVID, vs everything else that can go badly wrong in the miniscule rest of the pie chart. Singapore is massively vaccinated, and that’s the cause. So try to be like them, at least in this respect, ok? Yeah, I know: the US is not Singapore. Before you trot out some American-exceptionalist, hyper-patriot nonsense, let me point out that I completely understand public health campaigns must be culturally sensitive. Consider, for example, France and Germany, 2 of my favorite countries outside the US: • On the left, in German: “Impfen hilft, auch allen die du liebst”, or “Vaccination helps, also everyone you love”. • On the right, in French: “Oui, le vaccin put avoir des effets désirables”, or “Yes, the vaccine can have desirable effects”. Yes, by all means: do whatever the zeitgeist and l’esprit du temps nudge you to do, so long as you get your people vaccinated. So that’s the sitch. The sitch is bad. (Aside from the typically excellent French humor). ## Some things are happening (slowly, but at least happening) We are, in fact, developing Omicron-specific vaccines. Ever since back in 2021-Mar we’ve been working on variant-specific vaccines, starting with Delta. Again, even this CLBTNR has documented the then-variant-specific efforts by both Pfizer & Moderna and the FDA’s then-promise of rapid review, comparable to annual flu vaccines. Of course, since then things have moved on – and not in a good way – with the advent of the Omicron variant. From the New York Times comes a brief piece yesterday [1], documenting that clinical trials are happening for the Pfizer/BioNTech version specific to Omicron. It’s based on a joint Pfizer/BioNTech press release. [2] The trial is mid-sized (N = 1420$), not one of the monsters with 30,000 enrollees for the original vaccines. So it will go faster, even just for that reason. There are 3 cohorts: •$n = 615$: 2 doses current Pfizer vaccine followed by 2 doses Omicron-specific vaccine. I.e., this is for fully vaxed but not boosted people. •$n = 600$: 3 doses current Pfizer vaccine (fully vaxed and boosted), followed by either a fourth dose of the same or the new Omicron-specific vaccine. This answers the question of whether the new vaccine is much better than the old, in a fully vaxed and boosted population. •$n = 305$: Completely unvaccinated folks get 3 doses of the Omicron vaccine. This tells us about the vaccine naïve population, which at this point is still most of the world. (Sadly. To our collective moral discredit.) That’s important, because this is one of the populations where future variants will occur, so even selfish people should want to see them vaccinated! We can expect a readout of that trial before mid-year, followed by extremely rapid FDA/VRBPAC review and CDC/ACIP review. Of course, by next month Omicron will have burned its way through the US, so I sadly grant that this is not of much immediate utility. On the other hand, Pfizer and BioNTech are projecting a capacity to produce 4 billion doses this year, enough to re-vaccinte 1/4th of humanity in the first year of availability. So there’s that. Still, we’re doing something about Omicron (too slowly), and learning to get better for the next time (maybe just in time). ## What about ‘the next time’? And the next… and the next… and the next? I’m tired of the next pandemic always hanging over me! Can’t we do something about that? Why, yes. Yes, we can. That’s where today’s blog post comes in. NIAID issued some grants last year for research on pan-coronavirus vaccines, that will confer immunity to all variants of SARS-CoV2, including the ones that haven’t cropped up yet. Possibly also to the other 6 coronaviruses that infect humans (see this CLBTNR’s discussion here and here). Probably not (yet) also to the bajillions of coronaviruses currently in animal populations that might cause yet another pandemic someday, next time we do something stupid to an animal habitat. While we haven’t come across research reports from the original grantees, things have apparently been moving along swimmingly elsewhere in the time since 2020-Nov-01 when the grants were proposed. We’re now reaching the state of human clinical trials. The early reports were, frustratingly, non-technical and military (or derived exclusively from military sources). [3] [4] [5] • At least some of the research is happening at Walter Reed, which although definitely a military site, is also a very fine research institution. This effort is 2 years of work by approximately 2000 people, so it’s massive. • Animal challenge trials have included the Omicron variant as well as Delta and earlier variants, with good outcomes. • Phase 1 human clinical trials finished last month, but is as yet unpublished (and probably not yet fully analyzed). Recall that Phase 1 is very early, mostly just looking for a safety signal in a small group of people. Phase 2 will find doses and timing, then Phase 3 will verify efficacy. Those will happen in 2022. • It’s called a “spike ferritin nanoparticle”, and because the military requires acronyms, it’s known as SpFN. It’s variously (and maddeningly vaguely) described as like “a 24-sided soccer ball”, which presents mulitple different variant spike proteins on its faces. (That leads to 12-24 variants simultaneously, though I don’t see how it can be universal to all coronaviruses?) (Also parenthetically, a soccer ball is a Goldberg polyhedron, but has 32 faces instead of 24. And that’s as much as this nerd knows about sportsball, due to a lifelong sports aversion induced by beatings from jocks in middle & high school.) • It has an undemanding cold chain, unlike the mRNA vaccines: 36 - 46°F for up to 6 months and at room temperature for up to 1 month. • The best current guess at a dose schedule is 2 primers separated by 28 days and then a booster at 6 months after that. So… like the mRNA vaccines, pretty much. • There’s a “smaller” version of the vaccine, which concentrates on the Receptor Binding Domain (RBD) subset of the spike protein. It might be easier to manufacture, and appears to have about the same properties in preclinical trials. ## A deep(er) dive That’s about as much as we can learn from press releases and fawning interviews from the military press. For a deeper look, we’re going to have to find the scientists involved and see what they think. Our safari guides here will be: 1. Katelyn Jetelina’s blog Your Local Epidemiologist, who wrote about this 2021-Dec-26 [6]. Eric Topol of Scripps collaborated with Jetelina on this post. 2. The Science Translational Medicine publication of the preclinical data for the SpFN vaccine in primates [7]. 3. The PNAS publication of the preclinical data for the RFN vaccine in primates [8]. ### One approach: ‘elite neutralizers’ Some people, for reasons not understood, produce ‘broadly neutralizing antibodies’ (bnAbs) tht bind all over the relevant virus. In the case of SARS-CoV2 this means beyond the spike protein. About 10 research groups have found such bnAb examples, and isolated them for study. A group at Duke [9] has isolated an antibody with broad activity agains the RBD of broad families of sarebecoviruses (a viral subgenus containing SARS-CoV1 and SARS-CoV2, among other things you don’t want to hear about). Their antibody, DH1047, seems to be an excellent candidate for monoclonal antibody infusion therapy, if DH1047 can be manufactured at scale. ### How to cheat It’s ok, this is a virus. You can cheat against a virus. It’s allowed. It’s virtuous, even: it’s pikuach nefesh. Basically, they’ve built a ferritin nanoparticle (nanometer scale struture involving iron atoms), which has “24 sides like a soccer ball”. A soccer ball, as you of course all remember from gym class, is a Goldberg polyhedron (a very clever way of tesselating the unit sphere, mostly with regular hexagons plus 12 distinct pentagons). The soccer ball is the Goldberg polyhedron of order$G(1, 1)\$, which makes it a truncated icosahedron of 32 faces, not 24.

So “24 faces like a soccer ball” must be regarded as… illiteracy, of a sort. Whether it’s illiteracy of mathematics or of sports, we leave as an exercise for the reader.

There are various solids with 24 faces, though, so let’s let that one pass.

If you plant viral antigens on each of those faces (somehow!), you can expose the patient’s immune system to up to 24 variants. (More likely 8-12, so each variant is on 2 or 3 faces.) This has been done both with the full spike protein (SpFN) and with just the receptor binding doman (RBD, so it’s called the RFN vaccine). By that point, you’ve built what viruses can only regard as the vaccination death star.

In animal trials, they both induced antibody responses, and at sufficiently high doses also induced T-cell responses in a pseudovirus neutralization assay.

The human clincal trials started in 2021-Apr, with trial id NCT04784767 [10]. This proved somewhat difficult to recruit: participants must not have been previously vaccinated nor had COVID-19. So you had to find people who are still unvaccinated, but willing to participate in a vaccine trial! I’m pleasantly surprised they could do this.

That trial has apparently gotten to data lock, and is currently being analyzed. Chez Weekend, we’re all waiting excitedly. (Ok, not the cat. He’s… well, a cat. He’s too busy with more important matters, like guarding Château Weekend from birds, squirrels and other minuscule miscreants, as shown here. Occasionally, he theorizes that he can take down a wild turkey many times his size. He is incorrect, but we have prevented him from performing the relevant experiment.)

## The Weekend Conclusion

Ok, maybe we can process multiple variants in parallel: a 24-sided ferritin nanoparticle with 8-12 variant spike proteins/RBDs, at a redundancy factor of 2-3.

I guess it’s come to that: we have to be that clever to evade all the viruses we’re dumping into our population via climate change and animal habitat invasion.

We might not be this clever for the next one. Or we might be as bletcherously slow as we were for this one. Or we might be done in by great steaming buckets of superstitious vaccine defiance.

Heaven help us.

## Notes & References

1: B Mueller, “Pfizer and BioNTech begin a study of an Omicron vaccine, with initial results expected in the first half of the year.”, New York Times, 2022-Jan-25.

3: T Copp, “US Army Creates Single Vaccine Against All COVID & SARS Variants, Researchers Say”, Defense One, 2021-Dec-21.

4: Walter Reed Army Institute of Research, “Preclinical studies support Army’s pan-coronavirus vaccine development strategy”, US Army, 2021-Dec-16.

5: P Butler, “The Army’s ‘universal vaccine’ aims to end all COVID pandemics”, c _|_net, 2022-Jan-22.

6: K Jetelina, “Pan-coronavirus “super” vaccine”, Your Local Epidemiologist blog, 2021-Dec-26.

7: MG Joyce, “A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates”, Science Translational Medicine, 2021-Dec-16.

8: H King, et al., “Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques”, Proc Natl Acad Sci 118:38, 2021-Sep-21. DOI: 10.1073/pnas.2106433118.

9: D Martinez, et al., “A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice”, Science Translational Medicine, 14:629, 2021-Nov-02. DOI: 10.1126/scitranslmed.abj7125.

10: US Army Medical Research and Development Command, “SARS-COV-2-Spike-Ferritin-Nanoparticle (SpFN) Vaccine With ALFQ Adjuvant for Prevention of COVID-19 in Healthy Adults”, ClinicalTrials.gov, 2021-March-05.

Published Wed 2022-Jan-26

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